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| Pronunciation | /roʊˈlæpɪtænt/roh-LAP-i-tant |
| Trade names | Varubi (US), Varuby (EU) |
| Other names | SCH 619734 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a615041 |
| License data | |
| Routes of administration | By mouth (tablets),intravenous |
| Drug class | NK1 receptor antagonists,antiemetics |
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| Pharmacokinetic data | |
| Bioavailability | nearly 100% |
| Protein binding | 99.8% |
| Metabolism | CYP3A4 |
| Metabolites | C4-pyrrolidine-hydroxylated rolapitant (major) |
| Eliminationhalf-life | 169–183 hours |
| Excretion | Feces (52–89%), urine (9–20%)[1] |
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| ECHA InfoCard | 100.243.022 |
| Chemical and physical data | |
| Formula | C25H26F6N2O2 |
| Molar mass | 500.485 g·mol−1 |
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Rolapitant (INN,[2] trade nameVarubi/vəˈruːbi/və-ROO-bee in the US andVaruby in the European Union) is a drug originally developed bySchering-Plough and licensed for clinical development byTesaro, which acts as a selectiveNK1 receptor antagonist (antagonist for theNK1receptor).[3] It has been approved as a medication for the treatment ofchemotherapy-induced nausea and vomiting (CINV) afterclinical trials showed it to have similar or improved efficacy and some improvement in safety over existing drugs for this application.[4][5][6][7]
Rolapitant is used in combination with otherantiemetic (anti-vomiting) agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancerchemotherapy, including, but not limited to, highly emetogenic chemotherapy.[1] The approved antiemetic combination consists of rolapitant plusdexamethasone and a5-HT3 antagonist.[8]
Under the US approval, rolapitant is contraindicated in combination withthioridazine, whose inactivation could be inhibited by rolapitant.[1] Under the European approval, it is contraindicated in combination withSt. John's Wort, which is expected to accelerate inactivation of rolapitant.[8]
In studies comparing chemotherapy plus rolapitant, dexamethasone and a 5-HT3 antagonist to chemotherapy plusplacebo, dexamethasone and a 5-HT3 antagonist, most side effects had comparable frequencies in both groups, and differed more between chemotherapy regimens than between rolapitant and placebo groups. Common side effects included decreased appetite (9% under rolapitant vs. 7% under placebo),neutropenia (9% vs. 8% or 7% vs. 6%, depending on the kind of chemotherapy), dizziness (6% vs. 4%), indigestion andstomatitis (both 4% vs. 2%).[1]
Up to eightfold therapeutic doses have been given in studies without problems.[8]
Rolapitant moderately inhibits the liver enzymeCYP2D6. Blood plasma concentrations of the CYP2D6substratedextromethorphan have increased threefold when combined with rolapitant; and increased concentrations of other substrates are expected. The drug also inhibits the transporter proteinsABCG2 (breast cancer resistance protein, BCRP) andP-glycoprotein (P-gp), which has been shown to increase plasma concentrations of the ABCG2 substratesulfasalazine twofold and the P-gp substratedigoxin by 70%.[8]
Strong inducers of the liver enzymeCYP3A4 decrease thearea under the curve of rolapitant and itsactive metabolite (called M19); forrifampicin, this effect was almost 90% in a study. Inhibitors of CYP3A4 have no relevant effect on rolapitant concentrations.[8]
Both rolapitant and its active metabolite M19 block theNK1 receptor with highaffinity andselectivity: to block the closely related receptorNK2 or any other of 115 tested receptors andenzymes, more than 1000-fold therapeutic concentrations are necessary.[9]
Rolapitant is practically completely absorbed from the gut, independently of food intake. It undergoes no measurablefirst-pass effect in the liver. Highestblood plasma concentrations are reached after about four hours. When in the bloodstream, 99.8% of the substance are bound toplasma proteins.[8]
It is metabolized by the liver enzyme CYP3A4, resulting in the major active metabolite M19 (C4-pyrrolidine-hydroxylated rolapitant) and a number of inactive metabolites. Rolapitant is mainly excreted via the feces (52–89%) in unchanged form, and to a lesser extent via the urine (9–20%) in form of its inactive metabolites.Elimination half-life is about seven days (169 to 183 hours) over a wide dosing range.[8]
The drug is used in form of rolapitanthydrochloridemonohydrate, a white to off-white, slightlyhygroscopic crystalline powder. Its maximum solubility in aqueous solutions is atpH 2–4.[9]
